Hypertensive End Organ Damage: Protective Role of Ac-SDKP

Henry Ford Health System, Detroit MI

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Abstract

In hypertension, end organ damage (EOD) is due in part to the mechanical forces exerted by high blood pressure (BP); however, other mechanisms such as inflammation, oxidative stress, the RAS, and genetic predisposition, all play key roles in its pathogenesis. In hypertension, Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a naturally occurring peptide hydrolyzed mainly by ACE, reduces cardiovascular and renal inflammation and fibrosis without lowering BP. We have evidence that Ac-SDKP mediates some of the anti-fibrotic and anti-inflammatory effects of ACE inh and also prevents experimental autoimmune myocarditis in rats. Thus we propose to test the general hypothesis that in hypertension Ac-SOKP shifts the balance between proinflammatory/ pro-oxidative and anti-inflammatory/anti-oxidative systems in favor of the latter by decreasing innate and adaptive immunity and thus slowing the development of EOD. Furthermore, the effects of Ac-SOKP on BP and EOD are related to the degree of participation of innate and adaptive immunity in the pathogenesis of hypertension and EOD. This hypothesis will be studied in 3 aims. Aim I: In hypertensive Dahl salt-sensitive rats (Dahl SS) and in mice with systemic lupus erythematosus and hypertension, a model of autoimmune disease, Ac-SDKP acts as an immune modulator, reducing innate and adaptive immunity and thus EOD. Some of the effects of Ac-SDKP depend on the degree of participation of innate and adaptive immunity in the pathogenesis of hypertension and EOD. Aim II: The effects of ACE inh on the proinflammatory transcription factor NF-kB, T{H} cells and Treg cells are mediated by an increase in Ac-SDKP. Aim III: The effects of Ac-SDKP are multiphasic; central to these effects are decreases in: 1) the proinflammatory transcription factor NF-KB, 2) differentiation and maturation of dendritic cells (DCs), 3) DC transformation of T cells into effector T cells, and 4) T{H} cell proliferation, activation, migration, and differentiation into pro-inflammatory phenotypes. The effects of Ac-SDKP on T H are partly due to an increase in T{reg} cells. Project I is related to 1) III and IV which also study Dahl SS; 2) II and III, which also study the pathogenesis of EOD; and 3) II and IV which also study Ang II. Project I will use all 4 Cores.